Chronic liver disease is marked by the gradual destruction of liver tissue over time. Several liver diseases fall under this category, including cirrhosis and fibrosis, the latter of which is often the precursor to cirrhosis.
Cirrhosis is the result of acute and chronic liver disease and is characterized by the replacement of liver tissue by fibrotic scar tissue and regenerative nodules leading to a progressive loss of liver function. Fibrosis and nodular regeneration results in the loss of the normal microscopic lobular architecture of the liver. Fibrosis represents the growth of scar tissue resulting from, for example, infection, inflammation, injury, and even healing. Over time, the fibrotic scar tissue slowly replaces the normal functioning liver tissue resulting in a decreasing amount of blood flow to the liver leaving the liver incapable of fully processing nutrients, hormones, drugs, and poisons that are found in the bloodstream. More common causes of cirrhosis include alcoholism, hepatitis C viral infections, ingestion of toxins, and fatty liver, but many other possible causes also exist.
Chronic hepatitis C virus (HCV) infection and non-alcoholic steatohepatitis (NASH) are the two major causes of chronic liver disease in the United States estimated to affect between 3-5 million people. A rising concern is the continuously increasing number of U.S. citizens, currently numbering over 30 million, with obesity and metabolic syndrome that have non-alcoholic fatty liver disease (NAFLD) with approximately 10% who will eventually develop NASH.
Other bodily complications are a consequence of a loss of liver function. The most common complication of cirrhosis is a condition known as ascites, an accumulation of fluid in the peritoneal cavity, which can lead to an increased risk of spontaneous bacterial peritonitis possibly resulting in the premature death of the patient.
Other potentially life-threatening complications of cirrhosis include hepatic encephalopathy, a neuropsychotic abnormality resulting when toxic substances that normally are removed by the liver from blood begin to impair the proper functioning of brain cells. Hepatic encephalopathy manifests itself in a widely varying array of quantitative and qualitative distinct features, depending on the severity of impairment that occurs. The resulting cerebral dysfunction can be mild, manifesting itself through neuropsychiatric and psychomotor dysfunction, impaired memory, increased reaction time, sensory abnormalities and poor concentration. More severe manifestations resulting from hepatic encephalopathy include confusion, stupor, coma, and even eventual death. There are at least four theories for the pathogenesis of the condition. One theory suggests an energy failure in the cerebrum resulting from impaired glucose oxidative pathways caused by liver failure that leads to increased lactate synthesis in the brain. Another theory supports the notion of energy failure in the cerebrum but resulting instead from hypoglycemia and hypoxia caused by impaired liver function. A third theory suggests that the liver's failure to convert ammonia to urea or glutamine causes an increased concentration of the component in the bloodstream resulting in hyperammonemia in the brain eventually leading to the death of brain cells. A final theory for pathogenesis of hepatic encephalopathy is that any decrease in glucose utilization to provide energy to the brain is compensated for by the mobilization of amino acids that provide carbon skeletons as substrates for energy metabolism; however, the proteolysis of cerebral proteins to compensate for any energy loss ultimately proves destructive to proper functioning of the brain.
Yet another potentially life-threatening complication of cirrhosis includes esophageal varices or extremely dilated sub-mucosal veins in the esophagus that are susceptible to bleeding.
Once any cirrhosis or fibrosis has occurred in the liver, it is generally considered irreversible. Rather, conventional treatment focuses on preventing any further progression of cirrhosis in the liver and mitigating the complications that can arise from cirrhosis. In more advanced stages of cirrhosis, the only conventionally known treatment is a liver transplant.
The American Liver Foundation estimates that over 300,000 people in the United States are hospitalized each year as a result of cirrhosis of the liver. It is also estimated that 18,000 people are in need of liver transplants.
There remains a need in the art for a composition, formulation, and/or method of treatment for inhibiting fibrosis, preventing the development of cirrhosis, and possibly reversing development of the conditions altogether, which are responsible for many of the life-threatening complications associated with chronic hepatitis and chronic liver disease, such as, for example, excessive bleeding from esophageal varices, mental disturbances due to hepatic encephalopathy, ascites, liver cancer, and death due to exhaustion of liver function.
There remains a need in the art for a composition, formulation, therapy, and/or effective treatment to inhibit the progression of fibrosis in patients suffering from acute or chronic liver disease. There remains a further need in the art for a composition, formulation, therapy, or effective treatment to induce fibrosis reversal in patients suffering from acute or chronic liver disease. There remains a further need in the art for a composition, formulation, therapy or effective treatment to inhibit the progression of fibrosis and/or induce fibrosis reversal in patients suffering from acute or chronic liver disease that is substantially free of side effects.
HCV is a member of the hepacivirus genus of the Flaviviradae family of viruses. HCV can be classified into six genetic groups otherwise known as HCV clades that can further be classified into over 100 subtypes. The clades and subtypes differ from each other at the nucleotide level. Chronic hepatitis, experienced by well over 75% of persons infected, ultimately leads to cirrhosis of the liver in approximately 20% of those persons chronically infected and liver cancer leading to deaths of between 1% and 5% of those persons chronically infected. It is estimated that 3.5 million people have chronic hepatitis in the United States.
The pathogenesis of chronic HCV infection is associated with both a defective host antiviral immune response and an intrahepatic oxidative stress. Oxidative stress is possibly induced by the combined effects of an inflammatory response by the host and the HCV non-structural viral proteins. Additionally, oxidative stress and lipid oxidation are known to play a major role in fatty liver accumulation, which leads to necro-inflammation and necrosis of hepatic cells.
HCV non-structural viral proteins have been shown to cause activation of STAT-3 through oxidative stress and Ca2+ signaling. See Gong et al., “Human Hepatitis C Virus NS5A Protein Alters Intracellular Calcium Levels, Induces Oxidative Stress, and Activates STAT-3 and NF-kappa B,” Proc. Nat'l. Acad. Sci. USA, 98:9599-604 (2001). STAT-3 induction is influenced by the activation of cellular kinases, including p38 mitogen-activated protein kinase, JNK, JAK-2, and Src. In vivo experiments showed STAT-3 induction becomes inhibited in the presence of an antioxidant. It has been reported that HCV core protein increases radical oxygen species as well as products of lipid peroxidation and antioxidant gene expression. See Waris et al., “Hepatitis C Virus Constitutively Activates STAT-3 via Oxidative Stress: Role of STAT-3 in HCV Replication,” J. Virol., 79:1569-80 (2005). These processes are thought to contribute to fibrosis and carcinogenesis in hosts with chronic HCV infections. See Koike, “Molecular Basis of Hepatitis C Virus-Associated Hepatocarcinogenesis: Lessons from Animal Model Studies,” Clin. Gastroenterol Hepatol, 3:Sβ2-S135 (2005).
Fatty liver, also known as steatosis, is a disease that is characterized by an excessive amount of lipids accumulating in the liver. Fatty liver may develop due to medicine or alcohol use, viral or bacterial infections, or obesity. Fatty liver and conditions stemming from fatty liver include NASH, liver inflammation, cirrhosis, and liver failure. Steatohepatitis is inflammation of the liver resulting from fat accumulation in the liver.
NASH, also known as non-alcoholic fatty liver disease, is a hepatic disorder that is typically characterized by an alcoholic pathogenesis but without being influenced by alcohol consumption. Rather, NASH is directly related to the amount of fat in the liver. While there are many possible causes of NASH, the most likely causes that have been identified include obesity due to a poor diet, diabetes, long-term use of steroids, and the use of tetracycline. See, e.g., Bacon et al., “Nonalcoholic Steatohepatitis: An Expanded Clinical Entity,” Gastroenterology, 107:1103-91 (1994).
Recent studies have shown that oxidative stress and lipid peroxidation play a major role in fat accumulation in the liver, or steatosis, that leads to necroinflammation and necrosis of hepatic cells. Steatosis, and the ensuing lipid peroxidation, can lead to activation of stellate cells, the cells in the liver that are principally responsible for fibrogenesis. Some research has been directed towards identifying compositions comprising antioxidants that would be useful to treat the oxidative stress and/or lipid peroxidation associated with NASH.
Antioxidative therapy, directed towards mitigating the intrahepatic oxidative stress pathway, has been shown to have a beneficial effect on patients with chronic HCV infection. For example, U.S. Pat. No. 7,078,064 to Zabrecky discloses compositions having antioxidants that are useful for treating chronic liver disease, chronic hepatitis C virus infection, and non-alcoholic steatohepatitis. U.S. Pat. No. 6,069,167 to Sokol discloses the use of certain antioxidant agents including vitamin E, carotenoids, and selenium to treat cholestatic liver disease. U.S. Pat. No. 6,596,762 to Sokol discloses an antioxidant composition consisting of soluble vitamin E, mixed carotenoids, and selenium for the treatment of hepatic steatosis. These references report in vivo testing showing a high dosage of antioxidant administered to the subject relative to the subject's body weight. These references further show the administration therapies must be frequent and continue long-term.
The safety and efficacy of antioxidant therapy for patients with chronic HCV infection, in particular, for those patients who failed in interferon treatment has been reported in Gabby et al., “Antioxidant Therapy for Chronic Hepatitis C after Failure of Interferon: Results of Phase II Randomized, Double-Blind Placebo Controlled Clinical Trial,” World J. Gastroenterol., 13(4):5317-23 (2007). 100 patients suffering chronic HCV infection were enrolled in this double-blind, placebo controlled single-center trial. The study involved two treatment options involving 50 patients in each section. The first part tested the administration of oral and intravenous antioxidant preparations versus that of a placebo. The second part tested the administration of only the oral preparations versus a placebo. 25 patients were randomly assigned to each of the treatment group and the placebo group.
The oral and intravenous combinations are shown below:
Patient DoseOralIntraveneousComponentCombinationCombinationGlycyrrhiza500mg bid120mgSchizandrae500mg tid—Ascorbate2,000mg tid10,000mgL-Glutathione150mg tid750mgSilymarin250mg tid—Lipoic Acid150mg bid—d-Alpha Tocopherol800IU/d—B-comple—1mLPatients in the treatment groups of both studies received the oral combination once daily for 24 weeks. Patients in the treatment group of the first study additionally received the intravenous combination by injection with 400 mL of normal saline for infusion twice a week for the first ten weeks of the study. Patients in the placebo groups received pills resembling those of the treatment group and the normal saline intravenously.
The results of the study for each of the treatment group and the placebo group over the course of the study are given below.
Oral and Intravenous Antioxidant FormulationsOral Antioxidant Formulation OnlyALTASTHCV RNA SerumALTASTHCV RNA SerumIUIUlog(copies/ml)IUIUlog(copies/ml)WeekTreatedPlaceboTreatedPlaceboTreatedPlaceboTreatedPlaceboTreatedPlaceboTreatedPlacebo075.070.279.375.65.365.1686.476.770.274.24.845.161064.767.370.069.5————————12————5.205.2866.674.772.578.64.975.202464.875.061.778.55.085.0463.581.865.781.85.365.283262.768.258.666.95.305.1074.157.669.774.55.355.284066.662.166.967.55.355.3171.896.565.578.55.335.724863.058.373.169.35.715.3583.961.892.769.54.945.25The data shows that the combined use of oral and intravenous antioxidant formulations only mildly alleviate the intra-hepatic inflammatory response in patients suffering a chronic HCV infection while no effect is shown by using only the oral antioxidant treatment.
There remains a need in the art for an antioxidant formulation that can be administered as part of a treatment therapy to effectively prevent, retard, and/or reverse the effects of a chronic liver disease. There remains a further need in the art for an antioxidant composition that can be administered as part of a treatment therapy for acute or chronic liver disease that is substantially free of side effects. There remains a further need in the art for an antioxidant composition that can be administered as part of a treatment therapy for acute or chronic liver disease that is affordable.
Conventionally, the treatment of chronic HCV is a combination therapy including pegylated interferons and ribavirin. However, the response rate of the treatment's pharmacological efficacy and adverse effects is approximately 55% in patients infected with the genotype I virus. See Hughes et al., “Chronic Hepatitis C Virus Management: 2000-2005 Update,” Ann. Pharmacother, 40:74-82 (2006).
There remains a need in the art for a therapy to treat chronic HCV infected patients, especially for those patients who are non-responsive to conventional treatment therapies.
The use of alternative medicine is common in patients with chronic liver disease. For example, compositions comprising antiviral active components derived from herbal medicinal plants have traditionally been used in China for the treatment of hepatitis B virus, HCV, and HIV. Indeed, many modern drugs contain ingredients that are derived from herbs. The more conventionally termed alternative medicine, traditionally known as “folk” medicine, involves the use of herbal medicines in the care and treatment of the sick. Alternative medicine strategies have become more accepted in the western scientific medical community particularly as the development of pharmaceutical compounds have failed to keep pace with the ever-growing knowledge of pathogenesis pathways of various viral infections and diseases.
In fact, it has come to be known that many traditional herbal formulations lead to an in vivo response that can produce the pharmacological ingredient leading to the desired host response to combat the infection or disease. For example, the Chinese herbal medicine Aeginetiae Herba has traditionally been used to treat, among other things, liver disease. Aeginaetiae Herba is prepared from the dried whole plant of Aeginetia indica. A phosphate buffered saline extract from the seeds of Aeginetia indica has been shown to exhibit excellent carcinostatic effect possessing interleukin 2 and interferon y inducing potency effect. The Chinese herbal medicine Scutellariae Barbatae Herba derived from dried whole plants of Scutellaria rivularis have traditionally been used for the treatment of hepatitis and liver cirrhosis. The traditional Chinese practice of prescribing herbal medicines was in response to symptoms of a patient typically after a disease or agent itself had progressed to more advanced stages of development in the patient.
A method of producing an interferon inducer from the plants of the genus Cucurbitaceae, such as from a pumpkin seed, is disclosed in U.S. Pat. No. 4,421,746 to Kojima et al. U.S. Pat. No. 4,456,597 to Kojima et al. discloses an antiviral and anti-tumor activity of interferon inducers that are extracted from the flowers of Carthamus tinctorious. U.S. Pat. No. 4,469,685 also to Kojima et al. discloses that interferon inducers useful for the treatment of viral infections in humans may be extracted from the flowers of Lonicera japonica and the seeds of Plantago asiatica. 
Traditional Chinese and Ayurvedic therapies or treatment strategies have focused on the use of herbal formulations having many components, but it is not entirely clear whether a single component within the formulation or the combination of a collection of components within the formulation are responsible for the medicinal or therapeutic benefit. However, it is duly noted, that such a concept does run counter to the traditional western medicine concept of pharmacological treatment, which is focused on the delivery of a single compound or drug for the treatment of an infection, condition, disease, and the like.
There remains a need in the art to explore and identify alternative medicine treatments, either used alone or in a complimentary treatment strategy, generally for patients suffering from cirrhosis of the liver and, specifically, for patients having a chronic liver disease.